EP0820426B1 - SUBSTITUTED DIBENZ[a,f]AZULENES AND METHODS OF PREPARATION - Google Patents
SUBSTITUTED DIBENZ[a,f]AZULENES AND METHODS OF PREPARATION Download PDFInfo
- Publication number
- EP0820426B1 EP0820426B1 EP96908522A EP96908522A EP0820426B1 EP 0820426 B1 EP0820426 B1 EP 0820426B1 EP 96908522 A EP96908522 A EP 96908522A EP 96908522 A EP96908522 A EP 96908522A EP 0820426 B1 EP0820426 B1 EP 0820426B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- azulene
- dimethyl
- methoxy
- hydroxy
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title abstract description 29
- 238000002360 preparation method Methods 0.000 title description 8
- 150000001545 azulenes Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 122
- 230000035558 fertility Effects 0.000 claims abstract description 3
- 230000016087 ovulation Effects 0.000 claims abstract description 3
- 230000021595 spermatogenesis Effects 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- -1 nitro, hydroxy Chemical group 0.000 claims description 32
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000001475 halogen functional group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- UVXLYBHWFLUURH-UHFFFAOYSA-N 15-fluoro-1,9-dimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12(17),13,15-hexaen-5-ol Chemical compound CC1CC2C3=CC=C(F)C=C3CC2(C)CC2=CC(O)=CC=C12 UVXLYBHWFLUURH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- PTELFIHRIACAKO-UHFFFAOYSA-N 15-fluoro-5-methoxy-1,9-dimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12(17),13,15-hexaene Chemical compound CC1CC2C3=CC=C(F)C=C3CC2(C)CC2=CC(OC)=CC=C21 PTELFIHRIACAKO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003418 alkyl amino alkoxy group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- GHCYIEHYKGOAPI-UHFFFAOYSA-N 1,9-dimethyl-4,6-dinitrotetracyclo[9.7.0.03,8.012,17]octadeca-3,5,7,12,14,16-hexaen-5-ol Chemical compound CC1CC2C3=CC=CC=C3CC2(C)CC2=C1C=C([N+]([O-])=O)C(O)=C2[N+]([O-])=O GHCYIEHYKGOAPI-UHFFFAOYSA-N 0.000 claims description 3
- SMKQBBGGZNLKGZ-UHFFFAOYSA-N 1,9-dimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12,14,16-hexaen-5-amine Chemical compound CC1CC2C3=CC=CC=C3CC2(C)CC2=CC(N)=CC=C12 SMKQBBGGZNLKGZ-UHFFFAOYSA-N 0.000 claims description 3
- LFXRTDHSPRWACL-UHFFFAOYSA-N 5-methoxy-1-methyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,10,12,14,16-heptaene Chemical compound C1C=C2C3=CC=CC=C3CC2(C)CC2=CC(OC)=CC=C21 LFXRTDHSPRWACL-UHFFFAOYSA-N 0.000 claims description 3
- XLBNSTUYAZMVJK-UHFFFAOYSA-N 7-methoxy-1-methyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,10,12,14,16-heptaene Chemical compound C1C2(C)CC3=CC=CC=C3C2=CCC2=C1C=CC=C2OC XLBNSTUYAZMVJK-UHFFFAOYSA-N 0.000 claims description 3
- ZGQWVMOPEQSVOJ-UHFFFAOYSA-N N-(1,9-dimethyl-5-tetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12,14,16-hexaenyl)acetamide Chemical compound CC1CC2C3=CC=CC=C3CC2(C)CC2=CC(NC(C)=O)=CC=C12 ZGQWVMOPEQSVOJ-UHFFFAOYSA-N 0.000 claims description 3
- KZFOKWAXKWOQHQ-UHFFFAOYSA-N (1,9-dimethyl-5-tetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,10,12,14,16-heptaenyl) acetate Chemical compound CC1C=C2C3=CC=CC=C3CC2(C)CC2=CC(OC(C)=O)=CC=C12 KZFOKWAXKWOQHQ-UHFFFAOYSA-N 0.000 claims description 2
- DENWRUJQBLWHJK-UHFFFAOYSA-N 1,9-dimethyl-6-nitrotetracyclo[9.7.0.03,8.012,17]octadeca-3,5,7,12,14,16-hexaene-5,10-diol Chemical compound CC1C(O)C2C3=CC=CC=C3CC2(C)CC2=CC(O)=C([N+]([O-])=O)C=C12 DENWRUJQBLWHJK-UHFFFAOYSA-N 0.000 claims description 2
- ISSQPUNHWFEDDQ-UHFFFAOYSA-N 15-fluoro-5-methoxy-1,9-dimethyl-6-nitrotetracyclo[9.7.0.03,8.012,17]octadeca-3,5,7,12(17),13,15-hexaene Chemical compound C1C2(C)CC3=CC(F)=CC=C3C2CC(C)C2=C1C=C(OC)C([N+]([O-])=O)=C2 ISSQPUNHWFEDDQ-UHFFFAOYSA-N 0.000 claims description 2
- OAFIGRFYAIRIKJ-UHFFFAOYSA-N 5-fluoro-1,9-dimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12,14,16-hexaene Chemical compound CC1CC2C3=CC=CC=C3CC2(C)CC2=CC(F)=CC=C12 OAFIGRFYAIRIKJ-UHFFFAOYSA-N 0.000 claims description 2
- KJPLSWQKAWUXOK-UHFFFAOYSA-N 5-methoxy-1,9,10-trimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,10,12,14,16-heptaene Chemical compound CC1C(C)=C2C3=CC=CC=C3CC2(C)CC2=CC(OC)=CC=C21 KJPLSWQKAWUXOK-UHFFFAOYSA-N 0.000 claims description 2
- ABDIKHODZPADKU-UHFFFAOYSA-N 5-methoxy-1,9-dimethyl-6-nitrotetracyclo[9.7.0.03,8.012,17]octadeca-3,5,7,12,14,16-hexaen-10-ol Chemical compound C1C2(C)CC3=CC=CC=C3C2C(O)C(C)C2=C1C=C(OC)C([N+]([O-])=O)=C2 ABDIKHODZPADKU-UHFFFAOYSA-N 0.000 claims description 2
- XABCMWQGWGVXQA-UHFFFAOYSA-N 5-methoxy-1,9-dimethyl-6-nitrotetracyclo[9.7.0.03,8.012,17]octadeca-3,5,7,12,14,16-hexaene Chemical compound C1C2(C)CC3=CC=CC=C3C2CC(C)C2=C1C=C(OC)C([N+]([O-])=O)=C2 XABCMWQGWGVXQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 6
- IYQNWYHMIPWPNM-UHFFFAOYSA-N (5-methoxy-1,9-dimethyl-4-nitro-16-tetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12(17),13,15-hexaenyl) nitrate Chemical compound CC1CC2C3=CC=CC(O[N+]([O-])=O)=C3CC2(C)CC2=C([N+]([O-])=O)C(OC)=CC=C21 IYQNWYHMIPWPNM-UHFFFAOYSA-N 0.000 claims 1
- NLSGPZOFOCYTKK-UHFFFAOYSA-N (5-methoxy-1,9-dimethyl-6-nitro-16-tetracyclo[9.7.0.03,8.012,17]octadeca-3,5,7,12(17),13,15-hexaenyl) nitrate Chemical compound C1C2(C)CC(C(=CC=C3)O[N+]([O-])=O)=C3C2CC(C)C2=C1C=C(OC)C([N+]([O-])=O)=C2 NLSGPZOFOCYTKK-UHFFFAOYSA-N 0.000 claims 1
- XFYHSVRSZIOJHC-UHFFFAOYSA-N N-(1,9-dimethyl-5-tetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,10,12,14,16-heptaenyl)acetamide Chemical compound CC1C=C2C3=CC=CC=C3CC2(C)CC2=CC(NC(C)=O)=CC=C12 XFYHSVRSZIOJHC-UHFFFAOYSA-N 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical class C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 230000006698 induction Effects 0.000 abstract description 4
- 230000003389 potentiating effect Effects 0.000 abstract description 4
- 230000027455 binding Effects 0.000 abstract description 3
- 230000001850 reproductive effect Effects 0.000 abstract description 3
- 150000003431 steroids Chemical class 0.000 abstract description 3
- 108010085012 Steroid Receptors Proteins 0.000 abstract description 2
- 230000002513 anti-ovulatory effect Effects 0.000 abstract description 2
- 102000005969 steroid hormone receptors Human genes 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- 229910001868 water Inorganic materials 0.000 description 71
- 239000000203 mixture Substances 0.000 description 67
- 239000000243 solution Substances 0.000 description 66
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 56
- 239000003921 oil Substances 0.000 description 54
- 235000019198 oils Nutrition 0.000 description 54
- 239000002904 solvent Substances 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 39
- 238000004440 column chromatography Methods 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000007787 solid Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 29
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 239000003480 eluent Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 14
- 238000010561 standard procedure Methods 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 239000000284 extract Substances 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 7
- 229910017604 nitric acid Inorganic materials 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HPJYKMSFRBJOSW-JHSUYXJUSA-N Damsin Chemical compound C[C@H]1CC[C@H]2C(=C)C(=O)O[C@H]2[C@]2(C)C(=O)CC[C@@H]12 HPJYKMSFRBJOSW-JHSUYXJUSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000001665 trituration Methods 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- WNJNWDPUABOSOI-UHFFFAOYSA-N 5-methoxy-1,9-dimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12,14,16-hexaen-10-ol Chemical compound CC1C(O)C2C3=CC=CC=C3CC2(C)CC2=CC(OC)=CC=C21 WNJNWDPUABOSOI-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- QKCIWCFERNGBCE-UHFFFAOYSA-N 5-methoxy-1,9-dimethyltetracyclo[9.7.0.03,8.012,17]octadeca-3(8),4,6,12,14,16-hexaene Chemical compound CC1CC2C3=CC=CC=C3CC2(C)CC2=CC(OC)=CC=C21 QKCIWCFERNGBCE-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000003810 Jones reagent Substances 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- VETGQECQXHDROF-UHFFFAOYSA-N azulen-1-ol Chemical class C1=CC=CC=C2C(O)=CC=C21 VETGQECQXHDROF-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
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- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/62—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with more than three condensed rings
- C07C13/66—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with more than three condensed rings the condensed ring system contains only four rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/24—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
- C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
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- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
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- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
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- C07C43/21—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing rings other than six-membered aromatic rings
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- C07C43/02—Ethers
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
Definitions
- the present invention relates to novel chemical compounds of the following formula: wherein
- alkyl is defined as 1-6 carbons straight, branched or cyclic; halogen refers to fluorine, chlorine, bromine or iodine; alkoxy refers to groups derived from alcohols with straight or branched carbon chains having 1-4 carbons; acyloxy is defined as groups derived from aliphatic acids with straight or branched carbon chains having 2-6 carbons; alkenyl is defined as straight, branched or cyclic groups having 1-5 carbons which contain 1-4 degrees of unsaturation. All diastereomers which result from reduction of double bonds in the compounds as well as the substituents are included in this invention. The enantiomers of all possible diastereomers are also included in this invention.
- the compounds of this invention are capable of potent effects on steroid sensitive tissues and have demonstrated increased uterine weight, antiovulatory effects and potent steroid receptor binding.
- the compounds of this invention have therapeutic utility in reproductive applications such as fertility control, labor induction, ovulation induction, and spermatogenesis.
- the compounds of this invention can be expected to find utility in the treatment of progestin mediated maladies such as osteoporosis, hormone dependent carcinomas, uterine fibroids, precocious puberty, endometriosis, inflammatory dermatosis, arthritis, systemic lupus erythematosis, multiple sclerosis, type I diabetes, drug hypersensitivity, bronchial asthma, status asthmatics, allergic rhinitis, graft versus host disease and ulcerative colitis.
- progestin mediated maladies such as osteoporosis, hormone dependent carcinomas, uterine fibroids, precocious puberty, endometriosis, inflammatory dermatosis, arthritis, systemic lupus erythematosis, multiple sclerosis, type I diabetes, drug hypersensitivity, bronchial asthma, status asthmatics, allergic rhinitis, graft versus host disease and ulcerative colitis.
- the novelty of this invention resides in the non-steroidal structure of the compounds and their steroid-mimetic behavior.
- the compounds are tetracycles, where the first and the fourth rings are aromatic, six membered carbocycles, the second ring is a five membered carbocyclic ring, and the third ring is a seven membered carbocyclic ring wherein the degree of saturation varies.
- the compounds have an alkyl substituent at the ring junction of the second and the third ring.
- the invention relates to a novel series of tetracycles the pharmacological activity of which mimics that of a number of naturally occurring steroids, i.e. progestins and estrogens.
- steroids i.e. progestins and estrogens.
- Several of the intermediates formed in the preparation of the compounds of this invention as well as the processes of preparing them are novel and are considered to be part of the invention.
- R 1 is selected from the group consisting of hydrogen, halo, alkoxy and hydroxy
- R 2 is alkyl
- R 3 , R 4 and R 5 are selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxy, acyl, acyloxy, amino, acylamino, halo, nitro, hydroxy, and alkylaminoalkoxy
- R 6 and R 7 are hydrogen, alkyl, alkylene, hydroxy or carbonyl
- R 8 is hydrogen, hydroxy or acyloxy
- R 9 and R 10 are hydrogen or together form a double bond .
- the tetracycles of this invention are prepared as outlined in the reaction scheme described below.
- an appropriately substituted indanone (I) wherein R 1 is hydrogen, halogen or alkoxy; R 2 is a straight or branched chain alkyl group and R 3 , R 4 and R 5 are straight or branched chain alkyl, acylamino, alkoxy or hydroxy, is reacted with an appropriately substituted metal halide such as, for example, allylmagnesium bromide, vinyllithium or vinylmagnesium bromide and crotyl magnesium bromide, in a suitable solvent such as tetrahydrofuran (THF), diethyl ether or diisopropyl ether to give the substituted azulenes lla and llb (compound II).
- THF tetrahydrofuran
- diethyl ether diethyl ether or diisopropyl ether
- the reaction is generally carried out at a temperature between -78 degrees centigrade and room temperature for about 1-5 hours.
- the intermediate 2,3-dihydroindan-1-ol which forms is then reacted with a cyclizing agent such as p -toluenesulfonic acid or camphorsulfonic acid in a suitable solvent such as toluene, benzene or xylene or with thionyl chloride in a suitable solvent such as carbon tetrachloride, chloroform or methylene chloride to give compounds 11a and 11b.
- a cyclizing agent such as p -toluenesulfonic acid or camphorsulfonic acid
- a suitable solvent such as toluene, benzene or xylene
- thionyl chloride in a suitable solvent such as carbon tetrachloride, chloroform or methylene chloride
- R 6 , R 7 and R 8 in azulenes IIa and IIb will be hydrogen or alkyl, depending upon the particular organometallic compound employed.
- the mixture of azulenes IIa and IIb can be separated by techniques known to those skilled in the art such as, for example, chromatography and crystallization.
- Reduction of azulenes lla and llb with hydrogen in the presence of a catalyst such as palladium on carbon, palladium on calcium carbonate or palladium hydroxide on carbon in a suitable solvent such as ethyl acetate, ethanol, methanol or THF yields a mixture of diastereomeric derivatives IIIa and Illb.
- the hydrogenation step is generally carried out at room temperature at approximately 2-3 x 10 5 Pa (30-50 psi).
- the diastereomeric derivatives can be separated by techniques known to those skilled in the art such as chromatography and crystallization, for example.
- the alpha derivative is the stereoisomer wherein the hydrogen atoms are on the same side of the molecule as R 2 ; the beta derivative is the stereoisomer wherein the hydrogen atoms are on the side opposite from R 2 of the molecule.
- the alpha and beta isomers are obtained in the reaction.
- the alpha isomer unless otherwise indicated, is the isomer that is illustrated in the scheme from this point on, even though all of the following transformations can be performed on both the alpha and beta isomers.
- esters can also be prepared from compounds lla and llb wherein R 3 is hydroxy by similar acylation methods.
- a nitrating agent such as, for example, nitric acid in the presence of acetic acid in a suitable solvent such as acetic acid or propionic acid
- R 4 is nitro.
- the loss of the alkyl group can occur to form the phenol, depending upon the reaction conditions.
- the alkyl ketones (XXI) can be prepared from compound IIIa by reaction with boron trifluoride and an acid anhydride such as acetic anhydride.
- the amino compounds prepared above are diazotized to form the corresponding diazonium salts by means of a Sandmeyer reaction.
- the diazonium group can then be displaced with halogen using, for example, copper chloride or copper bromide, to form those compounds wherein R 3 is halo.
- Reaction of compound XXI with an oxidizing agent such as sodium hypobromite causes the alkyl carbonyl group to be replaced by a carboxyl group to yield those compounds wherein R 3 is a carboxyl group.
- the carbonyl group is converted to an olefin by reaction with an alkyllithium compound such as methyl or propyl lithium, for example, in a suitable solvent such as ether, cyclohexane or THF and then treated with an acid such as hydrochloric acid, hydrobromic acid or p -toluenesulfonic acid.
- the olefin can be reduced to an alkyl group by hydrogenation in the presence of a suitable catalyst such as palladium or platinum on charcoal. If the hydrogenation step is carried out under about 30 psi with 10% Pd/C only the exocyclic double bond is reduced. If the hydrogenation is carried out at 50 psi both double bonds are reduced to form the compounds of this invention.
- a suitable catalyst such as palladium or platinum on charcoal.
- R 12 is hydrogen or an alkyl group.
- Compounds Va and Vb of the present invention having a carbonyl substituent on the saturated seven membered ring are prepared by reacting compounds lla and llb wherein R 8 is hydrogen first with a reducing agent such as diborane, isoamyl borane or borane methyl sulfide, for example, followed by the addition of hydrogen peroxide in the presence of a base such as sodium hydroxide or potassium hydroxide to form the corresponding alcohol (IV).
- Oxidation of the alcohol with a suitable oxidizing agent such as, for example, Jones reagent, Collins reagent, pyridinium dichromate or pyridinium chlorochromate, results in the formation of the corresponding ketones Va and Vb.
- Compound II, wherein R 3 is hydroxy can be converted to the corresponding ester by reaction with an appropriate alkyl anhydride such as, for example, acetic anhydride or with an acyl halide such as, for example, acetyl chloride in the presence of a base such as triethylamine, diisopropylethylamine or pyridine.
- an appropriate alkyl anhydride such as, for example, acetic anhydride or with an acyl halide such as, for example, acetyl chloride in the presence of a base such as triethylamine, diisopropylethylamine or pyridine.
- a nitrating agent such as nitric acid in a suitable solvent such as acetic acid or propionic acid
- dehydrating agents such as acetic anhydride.
- the hydroxy group of the seven membered ring is also esterified under these conditions.
- the alkyl radical on the alkoxy group is partially demethylated during the reaction to form the corresponding phenol.
- the formation of dinitro side products may also occur.
- Phenol VI or compound III wherein R 3 is hydroxy, depending upon the reaction conditions employed, can be converted to the corresponding ether or ester derivative by first reacting the alcohol with a base such as sodium hydride or potassium hydride followed by reaction with the appropriate halide such as a dialkylphosphoryl halide, a dialkylaminoalkyl halide or a hydroxyalkyl halide such as, for example, dimethylaminoethyl chloride, diethylphosphoryl chloride or bromoethanol, or phenyltetrazoyl chloride.
- a base such as sodium hydride or potassium hydride
- the appropriate halide such as a dialkylphosphoryl halide, a dialkylaminoalkyl halide or a hydroxyalkyl halide such as, for example, dimethylaminoethyl chloride, diethylphosphoryl chloride or bromoethanol, or phenyltetrazoyl
- Compounds having a hydroxyalkyl group on the phenyl (D) ring can be prepared by reacting compounds XX with an organometallic compound such as a methyl or ethyl Grignard reagent, for example, under standard conditions for carrying out Grignard reactions. Reduction of the hydroxyalkyl derivatives using standard hydrogenolysis techniques results in compounds having an alkyl group on the D ring.
- organometallic compound such as a methyl or ethyl Grignard reagent
- indanone derivatives which are the starting materials for the preparation of the compounds of the present invention are either readily available or can be prepared by standard procedures known to those skilled in the art.
- a base such as, for example, sodium hydride
- an alkyl halide such as methyl iodide
- Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. intravenous, oral or parenteral.
- any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques.
- the carrier will usually comprise sterile water, though other ingredients may be employed, for example, to aid solubility or for preservative purposes; injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the pharmaceutical compositions will generally contain a dosage unit, e.g. tablet, capsule, powder and the like, from about 0.1 ⁇ g/kg to about 20 mg/kg and preferably from about 0.1 ⁇ g/kg to about 10 mg/kg of the active ingredient.
- the elemental analyses were measured on a Perkin Elmer 2400 spectrometer and are expressed in percentage by weight of each element per total molecular weight.
- the mass spectra (MS) were determined on a Finnigan Mat 8230 or a Finnigan MAT INCOS 50, single stage, quadrupole using desorption chemical ionization techniques. All column chromatography was run using Silica Gel 60, 230-400 mesh and any appropriate commercially available solvent. Unless otherwise noted, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to anyone skilled in the art of chemical synthesis.
- Acetic anhydride (41.75 mL, 0.46 mol) was added to a stirred solution of 2-[(3-aminophenyl)methyl]-2-methyl-1-indanone (37.00 g, 0.147 mol) in ethyl acetate (800 mL) and this mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate (600 mL) was added to the resulting mixture, followed by successive washes of the aqueous layer with ethyl acetate.
- p-Toluenesulfonic acid (0.25 g, 1.3 mmol) was added to a solution of 2-[(3-acetamidophenyl)methyl]-2-methyl-1-allyl-2,3-dihydroindan-1-ol (38.00 g, 0.113 mol) in toluene (3000 mL).
- the mixture was warmed to 80 °C on a rotary evaporator under reduced pressure for 1 h.
- the residual toluene was removed in vacuo and sat. NaHCO 3 (aq) (500 mL) and ethyl acetate (1000 mL) were added to the residue.
- the solvent was evaporated under reduced pressure and the remaining thionyl chloride was removed by azeotropic distillation using carbon tetrachloride to leave a residue.
- the residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired material. Cpd.
- the first product off the column was identified as the 10-nitro-5-nitrate ester of the starting material, and was isolated as colorless crystals mp 190-192°C.
- the second product off the column was the 8-nitro-5-nitrate ester of the starting material, which was isolated as a solid: mp 198-200 °C.
- This oil was purified by column chromatography on silica gel using 40% ethyl acetate/hexane as an eluent to give two major compounds.
- the first product that eluted off the column was the phenol, mp 173-174 °C.
- the second product was the methyl ether, which was recrystallized from ethyl acetate/hexane to give pure crystals, mp 152-154 °C.
- Crotyl bromide (2.0 g, 0.015 mol) was added to a suspension of magnesium (0.4 g) in diethyl ether (100 mL) and allowed to stand for 2 h.
- 2-[(3-Methoxyphenyl)methyl]-2-methyl-1-indanone (2.0 g, 0.0075 mol) was added to the resulting Grignard solution and the reaction was stirred overnight.
- the reaction was quenched with water and the resulting organic layer was washed with several portions of water, dried (MgSO 4 ) and concentrated in vacuo . The residue was dissolved in toluene (100 mL) and p -toluenesulfonic acid (10 mg) was added.
- the first product that eluted off the column was the 7-methoxy compound, mp 134-135°C; and the second product that eluted off the column was the 9-methoxy compound, mp 135-137°C, 1 H NMR (CDCl 3 ) 7.34-7.31 (multiplet, 1H), 7.25-7.14 (m, 3H), 7.04 (doublet, 1H), 6.74 (d,1H), 6.69 (doublet of doublets, 1H), 6.05 (dd, 1H), 3.88-3.80 (multiplet, 1H), 3.80 (singlet, 3H), 3.35-3.48 (m, 2H), 2.99 (d, 1H), 2.76 (d, 1H), 2.70 (doublet, 1H), 0.80 (s, 3H).
- the resulting oil was purified by column chromatography, and was dissolved in a suitable solvent (13.5 mL) and thionyl chloride (0.54 mL) was added. The reaction mixture was stirred for 5 h and quenched with aqueous sodium bicarbonate (sat) (20 mL), washed with water, dried and concentrated in vacuo . The residue was purified by any of the standard methods which include column chromatography and recrystallization to give the desired compound. Cpd.
- the resulting purple oil was purified by column chromatography on silica gel using methylene chloride/hexane (1:7) (that was treated with conc. ammonium hydroxide) as an eluent.
- the first compound off the chromatrography column was the 7-methoxy product, mp 153-154 °C, 1 H NMR (CDCl 3 ) 7.26 (doublet, 1H), 7.11 (triplet, 1H), 6.75 (multiplet, 4), 5.92 (doublet doublets, 1H), 4.07 (d, d 1H), 3.82 (singlet, 3H), 3.79 (singlet, 3H), 3.79 (multiplet, 1H), 3.41 (multiplet, 2H), 2.95 (doublet, 1H), 2.80 (doublet, 1H), 2.65 (doublet, 1H), 0.81 (singlet, 3H); and the second compound off the column was the 9-methoxy product, mp 149-151°C., 1 H NMR (CDC
- Lithium aluminum hydride (50 mg, 1.35 mol) was added in portions to a solution of 6,11a-dimethyl-9-methoxy-5-oxo-4b,5,6,11,11a,12-hexahydrobenz[a,f]azulene (300 mg, 0.98 mol) in diethyl ether (25 mL).
- the excess lithium aluminum hydride was quenched with water and the diethyl ether layer diluted with additional diethyl ether (50 mL).
- the combined organic layer was washed with water (3x), dried (MgSO 4 ) and concentrated in vacuo to give a solid. This solid was crystallized from hexane and ethyl acetate to give the title compound as a solid: mp 159-161 °C.
- Sodium hypobromite was prepared in situ by first dissolving NaOH (1.6 g, 0.04 mol) in water (13 mL) and cooling to -5 °C. Bromine (0.5 mL, 0.010 mol) was then added (dropwise) to this cooled solution, followed by the addition of dioxane (9 mL). The temperature of the freshly prepared hypobromite solution was kept at 0 °C.
- 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.8 g, 3.6 mmol) was added to a stirred suspension of 9-methoxy-11a-methyl-6,11,11a,12-tetrahydrodibenz[a,f]azulene (1.0 g, 3.6 mmol) in acetic acid (45 mL) and water (5 mL). The reaction mixture was stirred for 2h and an additional portion of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.8 g, 3.6 mmol) was added. The reaction mixture was stirred for another hour, poured into water (100 mL) and extracted with diethyl ether.
- a competitive binding assay was performed by mixing 3 H-promegestone with the receptor preparation and adding a known amount of unlabeled compound. This mixture was incubated at 4 °C for 18 h. The compounds bound to the receptor were separated from those which were free in solution using dextran coated charcoal and the amount of isotope bound to the receptor was determined by scintillation counting. The extent of the compound's interaction with the receptor is measured as the percent reduction in the total isotope bound caused by the unlabeled test compound as compared to the control levels.
- the receptor screen consists of measuring the reduction in the total isotope bound caused by the unlabeled test compound at 0.1 mmol, 1 mmol and 10 mmol final concentrations.
- the data represented in Table R list the IC 50 values of a number of the compounds.
- Compound IC 50 ( ⁇ M) 1 0.143 2 0.239 3 0.040 4 10.000 5 10.000 6 10.000 7 10.000 8 0.476 9 10.000 10 10.000 11 10.000 12 0.456 13 0.337 14 0.212 15 0.104 16 0.353 17 0.160 19 0.668 21 0.500 22 0.421 23 0.419 24 0.258 25 0.121 27 0.027 28 0.032 29 0.015 30 0.006 33 10.000 34 0.425 35 0.133 37 2.596 38 0.025 40 0.051 42 10.000 43 0.057 44 0.190 45 0.115 46 0.065 47 0.025 48 0.182 49 0.072 50 0.042 51 0.410 52 0.068 53 0.057 54 0.118 55 0.541 56 0.034 57 0.067 61 0.365 63 0.055 64 1.685 65 0.009 67 0.185 68 1.251 69 0.037 70 0.0420 71 0.4390 72 0.100 73 0.100
- Groups of mature, 150-175 g female rats are bilaterally ovariectomized under ether anesthesia. Seven days later, daily vaginal smears are obtained to verify complete castration. At least three consecutive diestrual smears indicate successful surgery. Rats are next injected subcutaneously on each of two successive days with 0.015 mg/kg estrone in 0.2 ml sesame oil per 200 g body weight to test their response to a standard estrogen. Smears made on the subsequent two days should be estrual (presence of cornified cells) on at least one of these days. Animals that respond to estrogen stimulation are rested for about one week until vaginal smears once again indicate a diestrual state.
- Test compounds are administered orally once daily for two days and vaginal smears are obtained as with the estrogen priming dose, to determine the incidence of estrual smears.
- the data in Table S is the dose in mg/kg, at which 2/2 rats show increased vaginal comification in a number of compounds.
- Cpd. # mg/kg 30 25 29 12 47 25 38 25 27 25 28 25 69 25 3 10
- 40 10 54 25 17 25 67 25 2 10 12 10 68 5 5 10 7 10
- Progestational activity was assessed as in the McGinty Test. The evaluation for endometrial proliferation was made according to a McPhail Index. Each slide was graded for each rabbit on a 0 (no response) - 4 (maximum response) scale. Cpd.#38 demonstrated a maximal response (4 - McPhail Index) at 40 mg/kg when administered subcutaneously.
- This assay is used to measure the sex steroid effects of compounds.
- the activity of compounds in this assay is an indication of their potential use as replacements for naturally occuring hormones in individuals with sex hormone deficiencies.
- T47D human breast carcinoma cells are grown in 96-well plates in phenol-red free nutrient media at 37° C for 48 hours. Conditioned media is removed and replaced with fresh media containing test compounds dissolved in DMSO (0.1% final concentration) and the cells are incubated for an additional 18 - 20 hours at 37° C. [ 3 H]-thymidine is added to each well and allowed to incorporate into DNA for 4 hours. Unlabeled thymidine is then added to terminate the reaction, and the cultures are then washed, trypsinized and harvested.
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Abstract
Description
-
- R1 is selected from the group consisting of hydrogen, halo, alkoxy (C1-C6) and hydroxy;
- R2 is alkyl (C1-C6);
- R3, R4 and R5 are selected from the group consisting of hydrogen, alkyl (C1-C6), alkoxy (C1-C6), benzyloxy, acyl (C2-C6), acyloxy (C2-C6), alkoxycarboxy wherein the alkoxy group has 1-5 carbon atoms, amino, acylamino (C2-C6), halo, nitro, hydroxy, cyano, alkylaminoalkoxy wherein the alkyl and alkoxy groups each contain 1-5 carbons, nitroso, dialkylphosphoryloxy, hydroxyalkyl (C1-C6), and phenyltetrazoyloxy;
- R6 and R7 are selected from hydrogen, alkyl (C1-C6), hydroxy, and when taken together alkylene (C1-C6) and carbonyl;
- R8 is selected from hydrogen, alkyl, hydroxy or acyloxy (C2-C6);
- R9 and R10 are hydrogen or together form a double bond, and R8 and R9 taken together form a carbonyl group, when R10 is hydrogen.
-
- For the purpose of this invention, alkyl is defined as 1-6 carbons straight, branched or cyclic; halogen refers to fluorine, chlorine, bromine or iodine; alkoxy refers to groups derived from alcohols with straight or branched carbon chains having 1-4 carbons; acyloxy is defined as groups derived from aliphatic acids with straight or branched carbon chains having 2-6 carbons; alkenyl is defined as straight, branched or cyclic groups having 1-5 carbons which contain 1-4 degrees of unsaturation. All diastereomers which result from reduction of double bonds in the compounds as well as the substituents are included in this invention. The enantiomers of all possible diastereomers are also included in this invention.
- The compounds of this invention are capable of potent effects on steroid sensitive tissues and have demonstrated increased uterine weight, antiovulatory effects and potent steroid receptor binding. The compounds of this invention have therapeutic utility in reproductive applications such as fertility control, labor induction, ovulation induction, and spermatogenesis. In addition to their reproductive uses, the compounds of this invention can be expected to find utility in the treatment of progestin mediated maladies such as osteoporosis, hormone dependent carcinomas, uterine fibroids, precocious puberty, endometriosis, inflammatory dermatosis, arthritis, systemic lupus erythematosis, multiple sclerosis, type I diabetes, drug hypersensitivity, bronchial asthma, status asthmatics, allergic rhinitis, graft versus host disease and ulcerative colitis.
- The novelty of this invention resides in the non-steroidal structure of the compounds and their steroid-mimetic behavior. Structurally, the compounds are tetracycles, where the first and the fourth rings are aromatic, six membered carbocycles, the second ring is a five membered carbocyclic ring, and the third ring is a seven membered carbocyclic ring wherein the degree of saturation varies. The compounds have an alkyl substituent at the ring junction of the second and the third ring.
- The prior art closest to the claimed compounds includes the following:
- 1. Homo-27-3,4-secogammacer-4(23)-enes; Y. Tsuda, T. Fujimoto, A. Morimoto, T. Sano, Chem. Pharm. Bull. 1975, 23 (6) 1336-46;
- 2. Dibenz[a,f]azulene-5(6H)-ones; H. Sasaki, T. Kitagawa, Chem. Pharm. Bull. 1983, 31 f(8), 2868-78; M. Koppes, H. Cerfontain, Recl. Trav. Chim. Pays-Bas, 1988, 107 (9), 549-62.
- 3. Dibenz[a,f]azulenes; Z. Chen, Shanxi Daxue Xuebao. Ziran Kexueban, 1985, 30, 53-65;
-
- The invention relates to a novel series of tetracycles the pharmacological activity of which mimics that of a number of naturally occurring steroids, i.e. progestins and estrogens. Several of the intermediates formed in the preparation of the compounds of this invention as well as the processes of preparing them are novel and are considered to be part of the invention.
- The preferred compounds of the invention are those wherein R1 is selected from the group consisting of hydrogen, halo, alkoxy and hydroxy; R2 is alkyl; R3, R4 and R5 are selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxy, acyl, acyloxy, amino, acylamino, halo, nitro, hydroxy, and alkylaminoalkoxy; R6 and R7 are hydrogen, alkyl, alkylene, hydroxy or carbonyl; R8 is hydrogen, hydroxy or acyloxy; and R9 and R10 are hydrogen or together form a double bond .
- The tetracycles of this invention are prepared as outlined in the reaction scheme described below. As can be seen from the reaction scheme, an appropriately substituted indanone (I), wherein R1 is hydrogen, halogen or alkoxy; R2 is a straight or branched chain alkyl group and R3, R4 and R5 are straight or branched chain alkyl, acylamino, alkoxy or hydroxy, is reacted with an appropriately substituted metal halide such as, for example, allylmagnesium bromide, vinyllithium or vinylmagnesium bromide and crotyl magnesium bromide, in a suitable solvent such as tetrahydrofuran (THF), diethyl ether or diisopropyl ether to give the substituted azulenes lla and llb (compound II). The reaction is generally carried out at a temperature between -78 degrees centigrade and room temperature for about 1-5 hours. The intermediate 2,3-dihydroindan-1-ol which forms is then reacted with a cyclizing agent such as p-toluenesulfonic acid or camphorsulfonic acid in a suitable solvent such as toluene, benzene or xylene or with thionyl chloride in a suitable solvent such as carbon tetrachloride, chloroform or methylene chloride to give compounds 11a and 11b. In the above reaction scheme at least one of R3 , R4 and R5 must be in the meta position relative to the methylene connecting group and be an electron donating group. R6, R7 and R8 in azulenes IIa and IIb will be hydrogen or alkyl, depending upon the particular organometallic compound employed. The mixture of azulenes IIa and IIb can be separated by techniques known to those skilled in the art such as, for example, chromatography and crystallization.
- Reduction of azulenes lla and llb with hydrogen in the presence of a catalyst such as palladium on carbon, palladium on calcium carbonate or palladium hydroxide on carbon in a suitable solvent such as ethyl acetate, ethanol, methanol or THF yields a mixture of diastereomeric derivatives IIIa and Illb. The hydrogenation step is generally carried out at room temperature at approximately 2-3 x 105 Pa (30-50 psi). The diastereomeric derivatives can be separated by techniques known to those skilled in the art such as chromatography and crystallization, for example.
- The alpha derivative is the stereoisomer wherein the hydrogen atoms are on the same side of the molecule as R2; the beta derivative is the stereoisomer wherein the hydrogen atoms are on the side opposite from R2 of the molecule. The alpha and beta isomers are obtained in the reaction. The alpha isomer, unless otherwise indicated, is the isomer that is illustrated in the scheme from this point on, even though all of the following transformations can be performed on both the alpha and beta isomers.
- Those compounds of derivative IIIa wherein R3 is methoxy or benzyloxy and R1 is hydrogen, hydroxy or halogen are reacted with boron tribromide in a suitable solvent such as methylene chloride, hexane or cyclohexane to yield the corresponding phenol (VI). Acylation of the phenol (VI) with an acid anhydride such as acetic anhydride or an acyl halide such as acetyl chloride in a suitable solvent such as chloroform, methylene chloride or THF yields the corresponding ester (VII). Esters can also be prepared from compounds lla and llb wherein R3 is hydroxy by similar acylation methods.
-
- Reaction of compound IIIa, wherein R3 is alkoxy or acetamido and R1 is hydrogen or halo, with a nitrating agent such as, for example, nitric acid in the presence of acetic acid in a suitable solvent such as acetic acid or propionic acid, results in the formation of those compounds wherein R4 is nitro. In the mono- or di-nitration step, where R3 is alkoxy, the loss of the alkyl group can occur to form the phenol, depending upon the reaction conditions. The alkyl ketones (XXI) can be prepared from compound IIIa by reaction with boron trifluoride and an acid anhydride such as acetic anhydride.
-
- Those amino compounds having a saturated seven membered ring are prepared in a similar manner using compounds IIIa and IIIb as the starting materials.
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- Those compounds having a saturated seven membered ring are prepared in a similar manner using compound III as the starting material.
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- Reaction of compound II, wherein R6 is hydrogen, with an oxidizing agent such as 1,3-dichloro-5,6-dicyano-1,4-benzoquinone or chloranil in a suitable solvent such as aqueous acetic acid or propionic acid, for example, results in the corresponding compound wherein R6 and R7 combine to form a carbonyl group. The carbonyl group is converted to an olefin by reaction with an alkyllithium compound such as methyl or propyl lithium, for example, in a suitable solvent such as ether, cyclohexane or THF and then treated with an acid such as hydrochloric acid, hydrobromic acid or p-toluenesulfonic acid. The olefin can be reduced to an alkyl group by hydrogenation in the presence of a suitable catalyst such as palladium or platinum on charcoal. If the hydrogenation step is carried out under about 30 psi with 10% Pd/C only the exocyclic double bond is reduced. If the hydrogenation is carried out at 50 psi both double bonds are reduced to form the compounds of this invention.
- In the above reaction scheme R12 is hydrogen or an alkyl group.
- Compounds Va and Vb of the present invention having a carbonyl substituent on the saturated seven membered ring are prepared by reacting compounds lla and llb wherein R8 is hydrogen first with a reducing agent such as diborane, isoamyl borane or borane methyl sulfide, for example, followed by the addition of hydrogen peroxide in the presence of a base such as sodium hydroxide or potassium hydroxide to form the corresponding alcohol (IV). Oxidation of the alcohol with a suitable oxidizing agent such as, for example, Jones reagent, Collins reagent, pyridinium dichromate or pyridinium chlorochromate, results in the formation of the corresponding ketones Va and Vb.
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- Compound II, wherein R3 is hydroxy, can be converted to the corresponding ester by reaction with an appropriate alkyl anhydride such as, for example, acetic anhydride or with an acyl halide such as, for example, acetyl chloride in the presence of a base such as triethylamine, diisopropylethylamine or pyridine.
- Reaction of compound IV, wherein R1 is hydrogen or halogen, with a nitrating agent such as nitric acid in a suitable solvent such as acetic acid or propionic acid, results in the formation of the corresponding aromatic nitro derivative using dehydrating agents such as acetic anhydride. The hydroxy group of the seven membered ring is also esterified under these conditions. The alkyl radical on the alkoxy group is partially demethylated during the reaction to form the corresponding phenol. The formation of dinitro side products may also occur. (Illustrated structures are derived from llb).
- Phenol VI or compound III wherein R3 is hydroxy, depending upon the reaction conditions employed, can be converted to the corresponding ether or ester derivative by first reacting the alcohol with a base such as sodium hydride or potassium hydride followed by reaction with the appropriate halide such as a dialkylphosphoryl halide, a dialkylaminoalkyl halide or a hydroxyalkyl halide such as, for example, dimethylaminoethyl chloride, diethylphosphoryl chloride or bromoethanol, or phenyltetrazoyl chloride. Those compounds having a phenyltetrazoyloxy group on the phenyl ring when reacted with a reducing agent such as hydrogen (Pd/C) lose the ester group to form the compounds having no substituent on the phenyl ring (D ring). Similar compounds can be prepared by carrying out a Birch reduction on the compounds having a dialkylphosphoryloxy group on the phenyl ring.
- Compounds having a hydroxyalkyl group on the phenyl (D) ring can be prepared by reacting compounds XX with an organometallic compound such as a methyl or ethyl Grignard reagent, for example, under standard conditions for carrying out Grignard reactions. Reduction of the hydroxyalkyl derivatives using standard hydrogenolysis techniques results in compounds having an alkyl group on the D ring.
- The indanone derivatives which are the starting materials for the preparation of the compounds of the present invention are either readily available or can be prepared by standard procedures known to those skilled in the art. For example, an appropriately substituted indanone is reacted with a base such as, for example, sodium hydride, and an alkyl halide, such as methyl iodide, to form the corresponding indanone wherein R2 is alkyl. Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. intravenous, oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients may be employed, for example, to aid solubility or for preservative purposes; injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions will generally contain a dosage unit, e.g. tablet, capsule, powder and the like, from about 0.1 µg/kg to about 20 mg/kg and preferably from about 0.1 µg/kg to about 10 mg/kg of the active ingredient.
- The following examples describe the invention in greater detail and are intended to illustrate the invention.
- Melting point determinations were carried out on a Thomas Hoover capillary melting point apparatus and are uncorrected. All compounds had spectra (Elemental Analysis, IR, 1H NMR, MS) consistent with their assigned structures. The infrared spectra (IR) were recorded on a Perkin Elmer 1430 spectrometer and are expressed in reciprocal centimeters. Nuclear magnetic resonance (NMR) spectra for hydrogen atoms were measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard on a Brucker WP-100 or a GE QE-300 spectrometer. The values are expressed in parts per million downfield from TMS. The elemental analyses were measured on a Perkin Elmer 2400 spectrometer and are expressed in percentage by weight of each element per total molecular weight. The mass spectra (MS) were determined on a Finnigan Mat 8230 or a Finnigan MAT INCOS 50, single stage, quadrupole using desorption chemical ionization techniques. All column chromatography was run using Silica Gel 60, 230-400 mesh and any appropriate commercially available solvent. Unless otherwise noted, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to anyone skilled in the art of chemical synthesis.
- The stereochemistry that is depicted in the schemes and designated in the examples is relative. No absolute determination of stereochemistry is claimed. When the substituent groups are on the same side of the ring system as R2, the compound is an a. When the opposite case occurs the compound is b. The substituents groups, which vary between examples are assumed to be hydrogen unless otherwise noted.
The general procedure according to Thompson (Tetrahedron Letters #52, pp 6489-6494, 1966) or Raju et al. (Indian J. Chem. B 26 (10) 914-916 1987) was used in the synthesis of the starting materials listed in Table A.R1 R3 R4 R2 H 3-NH2 H Me H 3-OMe H n-Pr H 3-OMe H Et H 3-OMe 5-OMe Me H 3-OMe H n-Bu H 3-OMe H Me 5-OMe 3-OMe H n-Pr 5-OMe 3-OMe H Et 5-OMe 3-OMe H Me 5-F H H Me 5-F 3-OMe H n-Pr - 2-[(3-Aminophenyl)methyl]indan-1-one (5.18 g, 22.0 mmol) in tetrahydrofuran (100 mL) was slowly added to a suspension of sodium hydride (2.20 g, 65.0 mmol), and tetrahydrofuran (100 mL) at room temperature and the mixture was stirred for 30 min. Methyl iodide (1.63 mL, 26.0 mmol) was added and the resulting mixture was stirred at room temperature for 5 h. Water (150 mL) was added, followed by methylene chloride (150 mL) and the resulting aqueous layer was washed with several portions of methylene chloride. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a solid: mp 95-98 °C, MS MH+ 252.
- Acetic anhydride (41.75 mL, 0.46 mol) was added to a stirred solution of 2-[(3-aminophenyl)methyl]-2-methyl-1-indanone (37.00 g, 0.147 mol) in ethyl acetate (800 mL) and this mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate (600 mL) was added to the resulting mixture, followed by successive washes of the aqueous layer with ethyl acetate. The combined organic extracts were washed with water (500 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an oil: 1H NMR (CDCl3) 7.7 (doublet, 1H), 7.55-7.15 (multiplet, 5H), 7.1 (doublet, 1H), 6.85 (doublet, 1H), 3.25 (doublet, 1H), 2.9 (doublet, 1H), 2.7 (doublet, 1H), 2.1 (singlet, 3H), 2.1 (doublet, 1H), 1.2 (singlet, 3H).
- 2-[(3-Acetamidophenyl)methyl]-2-methyl-1-indanone (38.00 g, 0.13 mol) in tetrahydrofuran (1.1 L) was slowly added to allylmagnesium bromide (388.6 mL, 0.39 mol) in tetrahydrofuran (100 mL) at 0 °C and the resulting mixture was stirred for 3 h. Water (750 mL) and ethyl acetate (750 mL) were added to the reaction and the resulting aqueous layer was washed with several portions of ethyl acetate. The combined organic extracts were washed with water (500 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound as a 50/50 mixture of diastereomers isolated as an oil: 1H NMR (CDCl3) (multiplet, 5H), 7.0-6.75 (multiplet, 3H), 6.1-5.6 (multiplet, 2H), 5.2 (multiplet, 3H), 3.2-2.3 (multiplet, 4H), 2.13 (singlet, 3H), 1.0 (singlet, 1.5H), 0.85 (singlet, 1.5H).
- p-Toluenesulfonic acid (0.25 g, 1.3 mmol) was added to a solution of 2-[(3-acetamidophenyl)methyl]-2-methyl-1-allyl-2,3-dihydroindan-1-ol (38.00 g, 0.113 mol) in toluene (3000 mL). The mixture was warmed to 80 °C on a rotary evaporator under reduced pressure for 1 h. The residual toluene was removed in vacuo and sat. NaHCO3(aq) (500 mL) and ethyl acetate (1000 mL) were added to the residue. The aqueous layer was washed (2x) with ethyl acetate. The combined organic extracts were washed twice with H2O (400 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (750 kg) using ethyl acetate/hexane 25/75 as an eluent, to give the title compound as a solid: mp 228.5-235 °C; MS MH+ 318.
- Allylmagnesium bromide (84 mL, 0.084 mol) was added to a solution of 5-fluoro-2-methyl-2-[(3-methoxyphenyl)methyl]indanone (12.0 g, 0.0422 mol) in diethyl ether (150 mL) and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with water and then washed with successive portions of ether. The combined ether extracts were then washed with H2O, dried (MgSO4) and concentrated in vacuo to give an oil. This oil was dissolved in carbon tetrachloride (300 mL) and thionyl chloride (15 mL) was added. The resulting solution was heated to reflux for 15 min and cooled to room temperature. The solvent was evaporated under reduced pressure and the remaining thionyl chloride was removed by azeotropic distillation using carbon tetrachloride to leave a residue. Said residue was purified by column chromatography on silica gel using hexane/CH2Cl2:50/50 as an eluent and by recrystallization from ethanol to give a solid: mp 173-175 °C.
The following general procedure was used in the synthesis of the compounds listed in Table B.
An appropriate allyl Grignard (20 mM) was added to a suitably substituted indanone derivative I (10 mmol) in an appropriate solvent such as diethyl ether (36 mL) and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with water and then washed with successive portions of an organic solvent . The combined organic extracts were washed with H2O, dried and concentrated in vacuo to give an oil. This oil was treated with either p-TsOH/toluene or SOCl2/CCl4, heated to reflux for 15 min and cooled to room temperature. The solvent was evaporated under reduced pressure and the remaining thionyl chloride was removed by azeotropic distillation using carbon tetrachloride to leave a residue. The residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired material.Cpd. R1 R2 R3 R4 mp°C C H N Empirical 3 H Me 9-OMe H 128-130 86.67 8.62 C21 H22 O 4 2-OMe Me 9-OMe H 149-151 82.33 7.27 C21 H22 O2 5 2-OMe Me 9-OMe H 169-170 82.60 7.38 C22 H24 O2 7 H Me 7-OMe H 184-185 86.71 7.67 C21 H22 O 11 H Me 7-OMe 9-OMe 192-195 82.22 7.58 C22 H24 O2 17 H Et 9-OMe H 78-81 86.78 8.25 C22 H24 O 22 2-OMe Et 9-OMe H 65-69 82.38 7.81 C23 H26 O2 38 H n-Pr 9-OMe H oil 84.88 8.72 C23 H26 O 42 2-OMe n-Pr 9-OMe H oil 86.64 7.82 C24 H28 O2 150 H n-Bu 9-OMe H 70-72 - 78.32 7.26 C24 H28 O 84 H n-Pr 9-NHAc H 217-219 86.81 8.45 4.66 C24 H27 NO - A solution of 9-acetamido-6,11,11a,12-tetrahydro-6,1 a-dimethyldibenz[a,f]azulene (15.0 g, 0.0473 mol) in ethyl acetate (150 mL) was added to a suspension of palladium hydroxide (0.60 g) in ethyl acetate (100 mL). The mixture was hydrogenated at 3 x 105 Pa (50 psi) for 48 h, followed by filtration through Celite 545 (25 g). The resulting solution was concentrated in vacuo to give the title compound as a white solid: 1H NMR (CDCl3) 7.3 (doublet, 1H), 7.2 (multiplet, 6H), 4.1 (quartet, 1H), 3.3 (multiplet, 2H), 2.9 (doublet, 3/4H), 2.8 (doublet, 1/4H), 2.6 (multiplet, 2H), 2.2 (singlet, 3H), 1.9 (multiplet, 1H), 1.7 (multiplet, 1H), 1.4 (doublet, 3/4H), 1.3 (doublet, 2 1/4H), 0.9 (singlet, 2 1/4H), 0.6 (singlet, 3/4H).
- The following general procedure was used in the synthesis of the compounds listed in Table C. The a and b designations in the table designate the relative positions of the ring juncture H and R2. In the alpha isomer both H and R2 are on the same side of the molecule and in the beta isomer they are on opposite sides. Where the compounds were isolated as a mixture of diastereomers, the designation is a, b.
A solution of an appropriate azulene derivative II (10 mmol), in a suitable solvent such as ethyl acetate (30 mL) was added to a suspension of a suitable catalyst such as palladium hydroxide-carbon in an appropriate solvent (21.2 mL). The suspension was reduced on a Parr hydrogenator at 3 x 105 Pa (50 psi). The resulting mixture was filtered through Celite, and concentrated in vacuo. This residue was purified using any of the standard techniques which include column chromatography and recrystallization to give the desired derivatives IIIa or IIIb.Cpd. R1 R2 R3 R4 R6 mp°C C H N Empirical 8 a H Me 9-OMe H Me 95-97 86.17 8.40 C21 H24 O 23 a,b H Et 9-OMa H Me 96-98 85.98 8.70 C22 H26 O 16 b H Me 9-OMe H Me 74-75 85.92 8.33 C21 H24 O 35 a,b H n-Pr 9-OMe H H oil 84.69 7.10 C22 H26 O 47 a 2-F Me 9-OMe H Me 70-71 84.74 8.78 C21 H23 FO 48 a,b H n-Pr 9-OMe H H 94-95 66.25 6.98 C23 H28 O 54 a H Me 7-OMe H Me 98-101 77.58 8.05 C21 H24 O 71 a 2-OMe n-Pr 9-OMe H H 125.5-127 81.30 7.75 C23 H28 O2 72 a 2-F n-Pr 9-OMe H H 100.5-102 78.39 7.89 C22 H25 FO 73 a 2-F n-Pr 7-OMe H H oil 71.90 7.33 C22 H25 FO 86 a H Me 7-OMe 9-OMe Me 99-100 75.78 7.13 C22 H26 O2 87 a H Me 7-OAc 9-OAc Me 121-123 84.77 7.66 C24 H26 O4 - 2-Fluoro-4b,5,6,11,11a,12-hexahydro-9-methoxy-6,11a-dimethyldibenz[a,f]azulene (3.0 g, 9.7 mmol) was dissolved in methylene chloride (250 mL) and cooled to -78°C in a dry ice-acetone bath. 1N Boron tribromide in CH2Cl2 (20 ml) was added and the reaction was allowed to warm to room temperature overnight. Excess boron tribromide was quenched with water and-the reaction was washed with saturated sodium bicarbonate solution, and successive portions of water. The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil. The oil was purified by column chromatography on silica gel using 15% ethyl acetate in hexane to give the title compound as an oil: MS MH+ 311.
- The following general procedure was used in the synthesis of the compounds listed in Table D
Boron tribromide (10 mmol ) was added to a solution of an appropriately substituted hexahydroazulene derivative (10 mmol) in methylene chloride (275 mL) at -78°C. After the addition was complete, the mixture was allowed to warm to room temperature for 12-72 h. The resulting mixture was partitioned between water and an appropriate organic solvent and the aqueous layer was washed with successive portions of ethyl acetate. The organic extracts were combined, dried (magnesium sulfate) and concentrated in vacuo to afford the desired compound.Cpd. R6 R2 mp°C C H Empirical 12 Me Me 89-91 85.96 8.15 C20 H22 O 40 H n-Pr 152-153 85.52 7.21 C21 H24 O 46 Me Et 106-109 81.34 7.80 C21 H24 O - To a solution of 9-hydroxy-6,11a-dimethyl-6,11,11a,12-tetrahydrodibenz[a,f] azulene (0.5 g, 0.0018 mol) and triethylamine 0.75 mL, 0.0054 mol.) in tetrahydrofuran (20 mL) was added dropwise acetyl chloride (0.2 mL, 0.0027 mol.). After stirring for 30 min. the reaction was quenched with water (0.5 mL) and diluted with 1N HCI (50 mL). The resulting mixture was extracted with ethyl acetate(2X100 mL) and the combined organic layers were washed with 1N HCI (100 mL) and then with water(2X100 mL). The organic layer was dried (MgSO4) and evaporated to give a solid. Trituration of this solid with methanol gave an analytical sample, mp 131-133 °C, 1H NMR (CDCl3) 7.35-7.38 (multiplet, 1 H), 7.11-7.22 (multiplet, 4H), 6.89-6.90 (doublet, 1H), 6.87 (singlet, 1H), 6.01-5.99 (doublet, 1H), 3.79-3.67 (multiplet, 1H), 3.45-3.42 (doublet, 1H), 3.01-2.96 (doublet, 1H), 2.81-2.76 (doublet, 1H), 2.66-2.71 (doublet, 1H), 2.29 (singlet, 3H), 1.42-1.40 (doublet, 3H), 0.86 (singlet, 3H).
- The following general procedure was used in the synthesis of the compounds listed in Tables E and F.
- To a solution of an appropriately substituted hydroxy azulene derivative (1.0 mM) and triethylamine (3.0 mM) in a suitable solvent (10 mL) was added dropwise an appropriate acyl halide (2.0 mM). The reaction was stirred for 30 min and then quenched with water (0.25 mL). After diluting with 1N HCI (25 mL) the mixture was extracted with several portions of an organic solvent. The combined organic layer was washed with water, dried and concentrated in vacuo. This residue was purified using any of the standard techniques which include column chromatography and/or recrystallization to give the desired azulene derivatives.
Cqd. R2 R3 mp°C C H Empirical 50 n-Pr 9-OAc oil 81.53 8.74 C23 H26 O2*1/4 H2O 108 Me 7-OAc 119-120 86.26 8.01 C21 H22 O2 Cpd. R1 mp°C C H Empirical 113 2-F 191-192 82.23 6.54 C21 H19 F O2 117 2-OMe 175-176 85.81 7.71 C22 H22 03 - 9-Methoxy-6,11a-dimethyl-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene (5.0 g, 17.1 mmol) was stirred with acetic anhydride (7 mL, 68.6 mmol) and boron trifluoride etherate (I mL, 8.1 mmol) in methylene chloride (150 mL) for 16 h. The solution was washed with water and the organic layers were dried (MgSO4) and concentrated in vacuo to give an oil. Said oil was purified by column chromatography on silica gel using ethyl acetate/hexane (1:4) as an eluent to give the title compound as a solid: mp 174-175.5 °C
- The following general procedure was used in the synthesis of the compound listed in Table G
An appropriately substituted azulene derivative llb (10 mmol) was stirred with acetic anhydride (30-50 mmol) and boron trifluoride etherate (4.75 mmol) in a suitable solvent for 16 h. The solution was washed with water and the organic layer was dried (MgSO4) and concentrated in vacuo to give a residue. Said residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired compound.Cpd. R3 R4 mp°C C H Empirical 44 9-OMe 8-Ac 157-158 77.15 7.20 C23H24O2 - Concentrated nitric acid (2.0 mL, 31.8 mmol) was added to a solution of 2-fluoro-4b,5,6,11,11a,12-hexahydro-9-methoxy-6,11a-dimethyldibenz[a,f]azulene (1.0 g, 3.2 mmol) in acetic acid (20 mL). The solution was heated to 40°C for one minute and then cooled to room temperature. The reaction was neutralized with saturated sodium bicarbonate solution and extracted into diethyl ether. The combined organic layers were washed with water, dried (MgSO4) and concentrated in vacuo to give an oil. Purification by column chromatography (silica gel) using ethyl acetate/hexane (1:4) as an eluent gave two major products. The second compound off the column was found to be the title compound, obtained as a light yellow oil: MS MH+ 356.
- The following general procedure was used in the synthesis of the compounds listed in Table H.
Nitric acid (10.0 mmol) was added to a solution of an appropriately substituted azulene derivative (II: 1.0 mmol) in acetic acid (6.6 mL) at room temperature. After addition was complete the reaction was stirred at room temperature for two hours. Saturated aqueous sodium bicarbonate and a suitable organic solvent were added to the reaction mixture; and the resulting aqueous layer was washed with successive portions of a suitable organic solvent. The organic extracts were combined, dried and concentrated in vacuo. The residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired material.Cpd. R3 R4 mp°C C H Empirical 91 8-NO2 9-NAc oil 71.56 6.32 C22 H24 N2 O3 102 9-OMe 8-NO2 90-94 56.38 4.94 C21 H23 N O3 - To a solution of 9-methoxy-6,11a-dimethyl-4b,5,6,11,11a,12-hexahydrodibenz[a,f] azulene (2.6 g, 8.9 mol) in acetic acid (250 mL) was added concentrated nitric acid (6 mL), followed by acetic anhydride (6 mL). The solution was stirred for 1 h, and the resulting solution was poured into water. This mixture was stirred for 1 h and extracted into methylene chloride. The combined organic layer was washed with sucessive portions of water, dilute sodium bicarbonate and water. The organic layer was dried (MgSO4) and concentrated in vacuo to an oil. Toluene was added, and the mixture was azeotropically distilled to remove any remaining acetic acid. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (2:3). The first product off the column, 4b,5,6,11,1a,12-hexahydro-9-methoxy-6,11a-dimethyl-8-nitrodibenz[a,f]azulene, was isolated as a crystalline solid, mp 90-94 °C. The second product off the column, 4b,5,6,11,11a,12-hexahydro-9-hydroxy-6,11a-dimethyl-8,10-dinitrodibenz[a,f]azulene was recrystallized from ethyl acetate/hexane to give pure product as a crystalline solid: mp 156-157 °C
- Concentrated nitric acid (20 mL) was added to a solution of 6,11 a-dimethyl-5-hydroxy-9-methoxy-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene (8.0 g, 26 mmol) in acetic acid (200 mL) and acetic anhydride (50 mL). The solution was stirred for 1 h and then poured into water. The resulting precipitate was filtered and purified by column chromatography on silica gel using ethyl acetate/hexane (2:3) as an eluent. The first product off the column was identified as the 10-nitro-5-nitrate ester of the starting material, and was isolated as colorless crystals mp 190-192°C. The second product off the column was the 8-nitro-5-nitrate ester of the starting material, which was isolated as a solid: mp 198-200 °C.
- Concentrated nitric acid (0.5 mL) was added to a solution of 6,11a-dimethyl-5-hydroxy-9-methoxy-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene (2.0 g, 6.5 mmol) in acetic acid (50 mL) and the resulting solution was heated to 50 °C for 1.0 minute and cooled to room temperature. The mixture was poured into dilute sodium bicarbonate solution and extracted with diethyl ether. The combined organic layers were washed with water, dried (MgSO4) and concentrated in vacuo to give an oil. This oil was purified by column chromatography on silica gel using 40% ethyl acetate/hexane as an eluent to give two major compounds. The first product that eluted off the column was the phenol, mp 173-174 °C. The second product was the methyl ether, which was recrystallized from ethyl acetate/hexane to give pure crystals, mp 152-154 °C.
- Concentrated hydrochloric acid (6 mL) was added to a solution of 9-acetamido-6,11a-dimethyl-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene (9.00 g, 0.028 mol) in methanol (25 mL) and the resulting mixture was heated and stirred at reflux for 6 h. Cold 5N sodium hydroxide (500 mL) was added to the mixture followed by washing the aqueous layer with successive portions of ethyl acetate. The combined organic extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give the title compound as a mixture of diastereomers isolated as a light yellow oil:1H NMR (CDCl3) (75/25 mixture of diastereomers.) 7.15 (multiplet, 4H), 6.95 (doublet, 1H), 6.55 (doublet, 1H), 6.45 (singlet, 1H), 3.5 (singlet, 2H), 3.4 (multiplet, 2H), 2.95 (doublet, 1H), 2.7-2.4 (multiplet, 2H), 2.6 (doublet, 1H), 1.9 (multiplet, 2H), 1.3 (doublet, 3/4H), 1.2 (doublet, 2 1/4H), 0.9 (singlet, 21/4H), 0.6 (singlet, 3/4H).
- The following general procedure was used in the synthesis of the compounds listed in Table I.
Concentrated hydrochloric acid (an excess) was added to a solution of an appropriately substituted acetamido derivative (10.0 mmol) in a suitable solvent such as methanol (9 mL) and the resulting mixture was heated and stirred at reflux for 6 h. Cold 5N sodium hydroxide ( 75 mL) was added to the mixture followed by washing the aqueous layer with successive portions of an organic solvent. The combined organic extracts were washed with water, dried and concentrated in vacuo. The residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired material.Cpd. R6 R3 R2 mp°C C H Empirical Formula 85 Me 9-NH2 n-Pr 97-100 81.80 8.31 C22H25N 96 H 7-NH2 Me oil 82.56 6.29 C19H21N - A solution of fluoroboric acid (48-50%) (1.437 mL) and water (0.60 mL) was added to a solution of 9-amino-6,11a-dimethyl-4b,5,6,11,11a,12-hexahydrodibenz[a,f] azulene (0.50 g, 2.0 mmol) dissolved in tetrahydrofuran (5 mL) and the resulting mixture was cooled to 0 °C. A saturated aqueous solution of sodium nitrate (I mL) was added dropwise to the cooled mixture at 0°C and the reaction mixture was stirred at 5°C for 30 min. The resulting precipitate was filtered, washed with methanol (5 mL) and ether (10 mL), and dried under reduced pressure. The solid residue was suspended in xylene (20 mL) and heated at reflux until the mixture turned very dark. The solvent was removed in vacuo and the resulting oil was purified by column chromatography on silica gel using methylene chloride/hexane 5:95 as an eluent to afford the title compound as a mixture of diastereomers isolated as a colorless oil: 1H NMR (CDCl3) (75/25 mixture of diastereomers) 7.1 (multiplet, 5H), 6.9 (multiplet, 2H), 3.3 (multiplet 2H), 3.0 (doublet, 1H), 2.8 (doublet, 1H), 2.4 (multiplet, 2H), 2.0 (multiplet, 2H), 1.3 (multiplet, 2H), 1.4 (doublet, 2H), 1.3 (doublet, 2 1/4H), 0.9 (singlet, 2 1/4H), 0.6 (singlet, 3/4H).
- The following general procedure was used in the synthesis of the compounds listed in Table J
A solution of an appropriate mineral acid (about 0.750 mL) and water (about 0.30 mL) was added to a solution of an appropriately substituted amino derivative (1 mmol), dissolved in a suitable solvent such as tetrahydrofuran (about 2.5 mL) and the resulting mixture was cooled to 0 °C. A saturated aqueous solution of sodium nitrate (0.5 mL) was added dropwise to the cooled mixture at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. The resulting precipitate was filtered, washed with a suitable solvent, and dried under reduced pressure. The solid residue was suspended in xylene (10 mL) and heated at reflux until the mixture turned very dark. The solvent was removed in vacuo and the residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired material.Cpd. R6 R3 R2 mp°C C H Empirical Formula 80 Me 9-Cl n-Pr 104-106 72.33 6.89 C22 H23 Cl 92 Me 9-Br n-Pr 105.5-109 82.92 6.99 C22 H23 Br 98 H 7-F Me 98-102.5 63.87 5.65 C19 H19 F 99 Me 9-1 n-Pr 112.5-116 86.05 8.65 C22 H23 I - Crotyl bromide (2.0 g, 0.015 mol) was added to a suspension of magnesium (0.4 g) in diethyl ether (100 mL) and allowed to stand for 2 h. 2-[(3-Methoxyphenyl)methyl]-2-methyl-1-indanone (2.0 g, 0.0075 mol) was added to the resulting Grignard solution and the reaction was stirred overnight. The reaction was quenched with water and the resulting organic layer was washed with several portions of water, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in toluene (100 mL) and p-toluenesulfonic acid (10 mg) was added. This mixture was stirred for 72 h and concentrated in vacuo to give a purple solid. This solid was dissolved into a minimum amount of boiling ethanol and ammonia was bubbled into this hot purple solution until said solution turned light yellow. Upon cooling, the title compound precipitated out of solution as colorless crystals: mp 158-160 °C.
- A solution of 2-[(3-methoxyphenyl]-2-methyl-1-indanone (1.0 g, 3.7 mmol) in 2 mL of diethyl ether was added via syringe at -120 °C to a solution of vinyl lithium (7.5 mmol) (Neumann and Seebach 1976 Tet. Letters. No. 52, 4839-4842). The mixture was allowed to warm slowly to 25 °C and quenched with water. The organic layer was washed with several portions of water, dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel using 15% ethyl acetate/hexane as an eluent. After removal of solvent the resulting oil was dissolved in methylene chloride (50 mL) and thionyl chloride (2.0 mL) was added. The reaction mixture was stirred for 5 h and quenched with aqueous sodium bicarbonate (sat) (20 mL), washed with water (3 X 50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluting with 10% methylene chloride in hexane to give the title compounds. The first product that eluted off the column was the 7-methoxy compound, mp 134-135°C; and the second product that eluted off the column was the 9-methoxy compound, mp 135-137°C, 1H NMR (CDCl3) 7.34-7.31 (multiplet, 1H), 7.25-7.14 (m, 3H), 7.04 (doublet, 1H), 6.74 (d,1H), 6.69 (doublet of doublets, 1H), 6.05 (dd, 1H), 3.88-3.80 (multiplet, 1H), 3.80 (singlet, 3H), 3.35-3.48 (m, 2H), 2.99 (d, 1H), 2.76 (d, 1H), 2.70 (doublet, 1H), 0.80 (s, 3H).
- The following general procedure was used in the synthesis of the compounds listed in Table K.
A solution of an appropriately substituted indanone derivative I (1 mmol) in a suitable solvent such as diethyl ether (0.55 mL) was added via syringe at -120 °C to a solution of vinyl magnesium bromide or vinyl lithium (2.0 mmol) (Neumann and Seebach 1976 Tet. Letters. No. 52, 4839-4842). The mixture was allowed to warm slowly to 25 °C and quenched with water. The organic layer was washed with several portions of water, dried and concentrated in vacuo. The resulting oil was purified by column chromatography, and was dissolved in a suitable solvent (13.5 mL) and thionyl chloride (0.54 mL) was added. The reaction mixture was stirred for 5 h and quenched with aqueous sodium bicarbonate (sat) (20 mL), washed with water, dried and concentrated in vacuo. The residue was purified by any of the standard methods which include column chromatography and recrystallization to give the desired compound.Cpd. R1 R3 R4 R2 mp C H N Empirical Formula 6 2-OMe 9-OMe H Me 153-154 81.53 7.26 C21 H22 O2 9 H 7-OMe 9-OMe Me 150-151 82.27 7.40 C21 H22 O2 27 H 9-OMe H n-Pr 73-74 86.34 7.79 C22 H24 O 29 H 7-OMe H n-Pr 123-124 86.26 7.82 C22 H24 O 37 2-OMe 9-OMe H Et 96-99 86.53 8.49 C22 H24 O1/2 H2 43 H 9-OMe H Et 108-110 82.82 7.07 C21 H22 O 52 H 7-OMe H Et 97-100 90.99 8.76 C21 H22 O 56 2-F 7-OMe H n-Pr 125-126 81.68 7.26 C22 H23 FO 57 2-F 9-OMe H n-Pr 112.5-114 80.49 7.02 C22 H23 FO 67 H 9-OMe H n-Bu 77-80 81.23 9.37 3.55 C23 H26 O 70 H 9-Me H Me 118-119 78.28 8.23 C20 H20 93 H 7-NAc H Me 182-184.5 82.97 7.17 4.39 C21 H21 N O 95 H 9-NAc H Me 216-219.5 86.66 8.23 5.40 C21 H21 NO - 1N Vinyl magnesium bromide (5.0 mL, 0.005 mol) was added to a solution of 2-methyl-2-[(3-methoxyphenyl)methyl]-5-methoxy-1-indanone (1.0 g, 3.4 mmol) in diethyl ether (50 mL). The mixture was stirred for 3 h and quenched with water. The resulting organic layer was washed with several portions of water, dried (K2CO3) and concentrated in vacuo. The resulting residue was dissolved in toluene (100 mL) and p-toluenesulfonic acid (-10 mg) was added. The solution was heated to reflux for one hour and concentrated in vacuo. The resulting purple oil was purified by column chromatography on silica gel using methylene chloride/hexane (1:7) (that was treated with conc. ammonium hydroxide) as an eluent. The first compound off the chromatrography column was the 7-methoxy product, mp 153-154 °C, 1H NMR (CDCl3) 7.26 (doublet, 1H), 7.11 (triplet, 1H), 6.75 (multiplet, 4), 5.92 (doublet doublets, 1H), 4.07 (d, d 1H), 3.82 (singlet, 3H), 3.79 (singlet, 3H), 3.79 (multiplet, 1H), 3.41 (multiplet, 2H), 2.95 (doublet, 1H), 2.80 (doublet, 1H), 2.65 (doublet, 1H), 0.81 (singlet, 3H); and the second compound off the column was the 9-methoxy product, mp 149-151°C., 1H NMR (CDCl3) 7.27 (doublet, 1H), 7.04 (doublet, 1H), 6.76-6.65 (multiplet, 4H), 5.91 (dd, 1H), 3.81 (multiplet, 1H), 3.80 (singlet, 3H), 3.79 (singlet, 3H), 3.45 (doublet, 1H), 3.35 (multiplet, 1H), 2.96 (doublet, 1H), 2.71 (doublet, 1H), 2.65 (doublet, 1H), 0.79 (singlet, 3H).
- A solution of 9-methoxy-6-methyl-11a-methyl-6,11,11a,12-tetrahydrodibenz[a,f] azulene (16.0 g, 55.1 mmol) in dimethoxyethane (150 mL) was heated to reflux. 1N Diborane in tetrahydrofuran (65 mL, 6.5 mmol) was added dropwise at a fast rate and the resulting mixture was heated at reflux for another 1/2 h. The reaction was cooled to room temperature and water (7 mL) was cautiously added, followed by 1 N sodium hydroxide (22 mL). 30% Hydrogen peroxide (8 mL) was added to the mixture and the resulting mixture was heated to 40 °C and immediately cooled to room temperature. The mixture was extracted with diethyl ether and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to give a solid. Trituration of said solid with hexane gave the title compound as a solid: mp 128-130 °C.
- The following general procedure was used in the synthesis of the compounds listed in Table L.
A solution of an appropriate azulene derivative (10 mmol) in a suitable solvent (27 mmol) was heated to reflux. 1N Diborane in tetrahydrofuran (1.17 mmol) was added dropwise at a fast rate and the resutling mixture was heated at reflux for another 1/2 h. The reaction was cooled to room temperature and water was cautiously added, followed by 1N sodium hydroxide. 30% Hydrogen peroxide was added to the mixture and the resulting mixture was heated to 40 °C and immediately cooled to room temperature. The mixture was extracted with an appropriate solvent and the organic layer was washed with water. The organic layer was dried and concentrated in vacuo. The residue was purified by any of the standard techniques which include column chromatography, recrystallization and trituration to give the desired compounds.Cpd. R1 R2 mp°C C H Empirical 19 2-OMe Me 118-119 78.01 7.97 C22 H26 O3 33 H Et 146-148 79.74 7.88 C22 H26 O21/2 H2O 45 2-F Me 114-115 86.29 8.69 C21 H23 F O2 - Jones reagent was added dropwise to a solution of 6,11a-dimethyl-5-hydroxy-9-methoxy-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene (2.0 g, 6.5 mmol) in acetone (50 mL) until the solution turned green. The excess reagent was quenched with ethanol and the mixture was filtered through magnesium sulfate. Evaporation of the solvent in vacuo gave a solid which was recrystallized from ethanol to give the title compound as a single diastereomer, mp 122-124 °C, 1H NMR (CDCl3) 7.19 (multiplet, 4H), 7.03 (doublet, 1 H), 6.83 (double doublets, 1H), 6.70 (doublet, 1H), 3.83 (singlet, 3H), 3.79 (singlet, 1H), 3.64 (quartet, 1H), 2.95 (doublet, 1H), 2.93 (doublet, 1H), 2.64 (doublet, 1H), 2.56 (doublet, 1H), 1.38 (doublet, 3H), 0.96 (singlet, 3H). The filtrate was concentrated in vacuo to give an oil. Said oil was purified by column chromatography on silica gel using 5% ethyl acetate in hexane as an eluent to give the minor diastereomer of the product, mp 132-133 °C, 1H NMR (CDCl3) 7.17 (multiplet, 3H), 7.05 (doublet, 1H), 6.96 (doublet, 1H), 6.72 (doublet doublets, 1H), 6.65 (doublet, 1H), 3.99 (quartet, 1H), 3.84 (singlet, 1H), 3.78 (singlet, 3H), 3.24 (doublet, 1H), 2.95 (doublet, 1H), 2.87 (doublet, 1H), 2.49 (doublet, 1H), 1.48 (doublet, 3H), 1.15 (singlet, 3H).
- The following general procedure was used in the synthesis of the compounds listed in Table M.
Jones reagent was added dropwise to a solution of an appropriately substituted 5-hydroxy azulene derivative IV (1.0 mmol in acetone, 7.7 mL) until the solution turned green. The excess reagent was quenched with ethanol and the mixture was filtered through magnesium sulfate. Evaporation of the solvent in vacuo gave a solid which was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired compounds.Cpd. R6 mp°C C H Empirical 75 H 198-200 78.12 9.98 C21H22O3 76 H 107-109 78.23 7.22 C21H22O3 77 Me 122-124 77.94 7.85 C22C24O3 - Lithium aluminum hydride (50 mg, 1.35 mol) was added in portions to a solution of 6,11a-dimethyl-9-methoxy-5-oxo-4b,5,6,11,11a,12-hexahydrobenz[a,f]azulene (300 mg, 0.98 mol) in diethyl ether (25 mL). The excess lithium aluminum hydride was quenched with water and the diethyl ether layer diluted with additional diethyl ether (50 mL). The combined organic layer was washed with water (3x), dried (MgSO4) and concentrated in vacuo to give a solid. This solid was crystallized from hexane and ethyl acetate to give the title compound as a solid: mp 159-161 °C.
- The following general procedure was used in the synthesis of the compound listed in Table N.
Lithium aluminum hydride (1.3 mmol) was added in portions to a solution of an appropriately substituted oxo azulene derivative Va or Vb (1 mmol) in a suitable solvent. The excess lithium aluminum hydride was quenched with water and the organic layer was diluted with solvent . The combined organic layer was washed with water and dried and concentrated in vacuo to give a residue. Said residue was purified by any of the standard techniques which include column chromatography and recrystallization to give the desired compounds.Cpd. R1 mp°C C H Empirical 78 OMe 108-110 82.40 7.89 C22H26O3 - 2-Fluoro-4b,5,6,11,11a,12-hexahydro-9-methoxy-6,11a-dimethyldibenz[a,f]azulene (3.0 g, 9.7 mmol) was dissolved in methylene chloride (250 mL) and cooled to -78°C in a dry ice-acetone bath. 1N Boron tribromide (10 mL) was added and the reaction was allowed to warm to room temperature overnight. Excess boron tribromide was quenched with water and the reaction was washed with saturated sodium bicarbonate solution, and successive portions of water. The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil. The oil was purified by column chromatography on silica gel using 15% ethyl acetate in hexane to give the title compound as an oil: MS MH+ 311.
- A solution of 2-fluoro-4b,5,6,11,11a,12-hexahydro-9-hydroxy-6,11a-dimethyldibenz[a,f]azulene (1.0 g, 3.4 mmol) in tetrahydrofuran (50 mL) was added dropwise to pentane washed sodium hydride (60 % in mineral oil: 0.4 g, 0.01 mol). Diethylchlorophosphate (0.7 g, 4.1 mmol) was added and the reaction was stirred for 0.5 h. The resulting mixture was diluted with ether, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) as an eluent to give the title compound as an oil: MSMH+ 433.
- A solution of 2-fluoro-4b,5,6,11,11a,12-hexahydro-9-hydroxy-6,11a-dimethyldibenz[a,f]azulene (0.9 g, 3.1 mmol) in dimethylformamide (10 mL) was added to sodium hydride (60% in mineral oil: 0.3 g, 7.3 mmol). The reaction was stirred for 15 min and 2-dimethylaminoethyl chloride (0.88 gm, 0.0062 mol) was added. The mixture was heated to 50 °C for 16 h and cooled to room temperature. Water was added and the mixture was extracted with several portions of diethyl ether. The combined organic layer was washed with water, dried (K2CO3) and concentrated in vacuo to give an oil. Said oil was purified by column chromatography on silica gel using methanol and methylene chloride (1:9) as an eluent to give the title compound as a light yellow oil: MS MH+ 368.
- The following general procedure was used in the synthesis of the compounds listed in Table O
A solution of an appropriately substituted hydroxy azulene derivative VI (1.0 mM) in a suitable solvent (3.5 mL) was added to sodium hydride (60% in mineral oil: 2.1 molar equivalents). The reaction was stirred for 15 min and an appropriate alkylating agent (2 mmol) was added. The mixture was heated to 50 °C for 16 h and cooled to room temperature. Water was added and the mixture was extracted with several portions of an organic solvent. The combined organic layer was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography to give the desired compound.Cpd. R6 R3 R2 mp°C C H Empirical 51 Me 9-O(CH2)2NMe2 Me oil 86.64 7.60 C24H31NO 1/4 H2O 68 H 9-O(CH2)2NEt2 n-Pr oil 85.66 7.82 C27H37NO - A solution of 2-fluoro-4b,5,6,11,11a,12-hexahydro-9-hydroxy-6,11a-dimethyldibenz [a,f]azulene (1.0 g, 3.4 mmol) in dimethylformamide (10 mL) was added to a stirred suspension of pentane washed sodium hydride (60% in mineral oil) (0.4 g, 0.01 mol). After 15 minutes, 5-chloro-1-phenyl-1H-tetrazole (0.67 9, 3.7 mmol) was added and the resulting mixture was heated to 50 °C for 3 h and cooled to room temperature. The excess sodium hydride was quenched with water and the mixture extracted with diethyl ether. The combined organic layer was washed with water (3 x 50 mL), dried (MgSO4) and concentrated in vacuo to give an oil. This oil was purified by column chromatography on silica gel using ethyl acetate/hexane (15:85) as an eluent to give the title compound as a foam: MS MH+ 441.
- A solution of 6,11a-dimethyl-2-fluoro-9-(1-phenyl-5-tetrazolyl)-oxy-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene (0.5 g, 1.1 mmol) in tetrahydrofuran (60 mL) was added to 10% Pd-charcoal (100 mg) in a Parr bottle. The bottle was filled with hydrogen to 3 x 105 Pa (50 psi) and shaken for 6 h. The mixture was filtered through Celite and the solvent was concentrated in vacuo to give an oil. The oil was dissolved in hexane and passed through a bed of silica gel (in a Pasteur pipet) using hexane as an eluent. Evaporation of the solvent gave the title compound as a clear oil: MS 356 (MH+).
- Sodium hypobromite was prepared in situ by first dissolving NaOH (1.6 g, 0.04 mol) in water (13 mL) and cooling to -5 °C. Bromine (0.5 mL, 0.010 mol) was then added (dropwise) to this cooled solution, followed by the addition of dioxane (9 mL). The temperature of the freshly prepared hypobromite solution was kept at 0 °C. A solution of 8-acetyl-4b,5,6,11,1a,12-hexahydro-6,11a-dimethyl-9-methoxydibenz[a,f]azulene (1.0 g, 3.0 mmol) in aqueous dioxane (53 mL, 77%) was cooled at 8°C and stirred with a mechanical stirrer. The sodium hypobromite solution was added to the stirred solution and the temperature was kept at 10 °C for one hour. The mixture was then allowed to warm to room temperature and stirred for 3 h. The excess sodium hypobromite was destroyed by adding a solution of sodium bisulfite (0.5 g) in water (4 mL). The resulting mixture was heated to reflux for 15 minutes and acidified while hot with 2 mL of concentrated hydrochloric acid. Upon cooling, the mixture was extracted with diethyl ether. The combined organic extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give an oil. This oil was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) as an eluent to give the title compound as a solid: mp 153-154 °C.
- To a solution of 6,11,11a,12-tetrahydro-9-methoxy-11a-methyl-6-oxodibenz[a,f]azulene (2.0 g, 6.9 mmol) in diethyl ether (150 mL) was added 1.4 N methyl lithium in diethyl ether (7 mL). The reaction mixture was stirred for 10 min and quenched with water. The diethyl ether layer was washed with successive washes of water, 1 N hydrochloric acid and water, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave an oil. This oil was dissolved in methylene chloride and heated at reflux with 4Å molecular sieves for 16 h. The mixture was filtered and the solvent removed in vacuo to give a solid. The solid was dissolved in methylene chloride and passed through a plug of silica gel. The solvent was removed in vacuo and the residue was recrystallized from methanol to give the title compound as a solid: mp 171-173 °C.
- 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.8 g, 3.6 mmol) was added to a stirred suspension of 9-methoxy-11a-methyl-6,11,11a,12-tetrahydrodibenz[a,f]azulene (1.0 g, 3.6 mmol) in acetic acid (45 mL) and water (5 mL). The reaction mixture was stirred for 2h and an additional portion of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.8 g, 3.6 mmol) was added. The reaction mixture was stirred for another hour, poured into water (100 mL) and extracted with diethyl ether. The combined organic layers were washed with successive portions of 1 N sodium hydroxide and water, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel using methylene chloride as an eluent followed by trituration with methanol to give the title compound as a solid: mp 122-123 °C.
- 6,11,11a,12-Tetrahydro-6-methenyl-9-methoxy-11a-methyldibenz[a,f]azulene (0.5 g, 1.7 mmol) was suspended in tetrahydrofuran (150 mL) containing 10% palladium carbon (25 mg). The mixture was reduced at 2 x 105 Pa (30 psi) on a Parr hydrogenator. After 16 h the mixture was filtered through celite and concentrated in vacuo. The residue was triturated with methanol to give a solid, which was recrystallized from methanol to give the title compound as a solid: mp 140-142°C.
- 7-Methoxy-11a-methyl-6,11,11a,12-tetrahydrodibenz[a,f]azulene (3.0 g, 0.0109 mol) was suspended in ethyl acetate (250 mL) containing palladium/calcium carbonate (100 mg). The mixture was reduced at 2 x 105 Pa (30 psi) on the Parr hydrogenator. After 8 h the reaction was filtered through celite and concentrated in vacuo. Recrystallization of the resulting solid from methanol yielding the title compound as a solid: mp 127-129 °C.
- 6,11,11a,12-Tetrahydro-6-methenyl-9-methoxy-11a-methyl-dibenz-[a,f]azulene (1.0 g, 3.5 mmol) was suspended in ethyl acetate (250 mL) containing palladium on carbon (10%, 200 mg). The mixture was reduced at 3 x 105 Pa (50 psi) on the Parr hydrogenator over 3 h. The reaction was filtered through celite and concentrated in vacuo to give an oil. Trituration of said oil with methanol gave the title compound as a solid m.p. 93-95 °C.
- Small portions of sodium metal were added to a solution of 9-(6,11,11a,12-tetrahydro-6,11a-dimethyl)dibenz[a,f]azulenyl diethyl phosphoric acid (1.5 g, 36 mmol), liquid ammonia (75 mL) and ether (15 mL) until the characteristic blue color persisted for 15 min. The ammonia was allowed to evaporate and the resulting residue was extracted several times with hexane and the combined organic extracts were washed with water. The combined organic layer was dried with MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane as an eluent to give the title compound as an oil.
Anal. Calc'd for C20H22 C, 91.55; H, 8.45 Found C, 91.51; H, 8.21 - The following general procedure was used to synthesize the compound listed in Table P.
Small portions of sodium metal were added to a solution of an appropriately substituted dialkyl phosphoric acid derivative (10 mmol), liquid ammonia (20 mL) and ether (4.2 mL) until the characteristic blue color persisted for 15 min. The ammonia was allowed to evaporate and the resulting residue was extracted several times with a suitable solvent followed by washing of the combined organic layer with water. The organic layer was dried with an appropriate drying agent and concentrated in vacuo. The residue was purified by column chromatography and/or recrystallization to give the desired compound.Cpd. R2 mp°C C H Empirical 53 Et oil 85.98 8.27 C21 H24 - The procedure used was essentially that of J. L. McGuire, C. D. Bariso and A. P. Shroff, Biochemistry, 13, 319 (1974).
- Uteri from New Zealand rabbits (1.5 to 2.5 kg) were placed in a cold buffer A (0.01 mol Tris-HCI, pH 8.0, 0.001 mol EDTA, 0.25 mol sucrose). The uteri were minced, washed and homogenized in cold buffer A. The homogenate (2 g wet tissue/mL buffer) was centrifuged at 200,000 X g for 1 h at 4 °C. The high speed supernatant fraction was used as the receptor preparation.
- A competitive binding assay was performed by mixing 3H-promegestone with the receptor preparation and adding a known amount of unlabeled compound. This mixture was incubated at 4 °C for 18 h. The compounds bound to the receptor were separated from those which were free in solution using dextran coated charcoal and the amount of isotope bound to the receptor was determined by scintillation counting. The extent of the compound's interaction with the receptor is measured as the percent reduction in the total isotope bound caused by the unlabeled test compound as compared to the control levels. The receptor screen consists of measuring the reduction in the total isotope bound caused by the unlabeled test compound at 0.1 mmol, 1 mmol and 10 mmol final concentrations. The data represented in Table R list the IC50 values of a number of the compounds.
Compound IC 50 (µM) 1 0.143 2 0.239 3 0.040 4 10.000 5 10.000 6 10.000 7 10.000 8 0.476 9 10.000 10 10.000 11 10.000 12 0.456 13 0.337 14 0.212 15 0.104 16 0.353 17 0.160 19 0.668 21 0.500 22 0.421 23 0.419 24 0.258 25 0.121 27 0.027 28 0.032 29 0.015 30 0.006 33 10.000 34 0.425 35 0.133 37 2.596 38 0.025 40 0.051 42 10.000 43 0.057 44 0.190 45 0.115 46 0.065 47 0.025 48 0.182 49 0.072 50 0.042 51 0.410 52 0.068 53 0.057 54 0.118 55 0.541 56 0.034 57 0.067 61 0.365 63 0.055 64 1.685 65 0.009 67 0.185 68 1.251 69 0.037 70 0.0420 71 0.4390 72 0.100 73 0.100 74 0.199 75 0.555 76 10.000 77 10.000 78 10.000 80 10.000 81 0.082 82 0.099 83 1.969 84 0.161 85 0.019 86 1.675 87 0.729 88 0.034 89 0.137 90 0.032 91 0.115 92 0.139 93 10.000 95 1.768 96 0.034 97 10.000 98 0.0600 99 0.090 101 0.621 102 1.470 105 0.676 106 0.105 107 0.678 108 0.029 109 1.254 113 0.006 117 0.093 - Groups of mature, 150-175 g female rats are bilaterally ovariectomized under ether anesthesia. Seven days later, daily vaginal smears are obtained to verify complete castration. At least three consecutive diestrual smears indicate successful surgery. Rats are next injected subcutaneously on each of two successive days with 0.015 mg/kg estrone in 0.2 ml sesame oil per 200 g body weight to test their response to a standard estrogen. Smears made on the subsequent two days should be estrual (presence of cornified cells) on at least one of these days. Animals that respond to estrogen stimulation are rested for about one week until vaginal smears once again indicate a diestrual state. Test compounds are administered orally once daily for two days and vaginal smears are obtained as with the estrogen priming dose, to determine the incidence of estrual smears. The data in Table S, is the dose in mg/kg, at which 2/2 rats show increased vaginal comification in a number of compounds.
Cpd. # mg/kg 30 25 29 12 47 25 38 25 27 25 28 25 69 25 3 10 40 10 54 25 17 25 67 25 2 10 12 10 68 5 5 10 7 10 - The procedure used was essentially that of M. K. McPhail, J. Physiology, 83, 145 (1934). Groups of immature female white rabbits (750-950 g) were primed with a daily subcutaneous injection, for 6 days, with 5 micrograms of 178-estradiol in 0.2 ml of sesame oil. Starting on the 7th day, they received the test compound daily for five days in the appropriate vehicle. The rabbits were sacrificed approximately 24 hours after the last administration, and the uteri were excised, cleaned and weighed. Portions of both uterine horns were fixed in 10% neutral formalin, sectioned at 6 µM and stained with hematoxylin and eosin. Progestational activity was assessed as in the McGinty Test. The evaluation for endometrial proliferation was made according to a McPhail Index. Each slide was graded for each rabbit on a 0 (no response) - 4 (maximum response) scale.
Cpd.#38 demonstrated a maximal response (4 - McPhail Index) at 40 mg/kg when administered subcutaneously. - This assay is used to measure the sex steroid effects of compounds. The activity of compounds in this assay is an indication of their potential use as replacements for naturally occuring hormones in individuals with sex hormone deficiencies.
T47D human breast carcinoma cells are grown in 96-well plates in phenol-red free nutrient media at 37° C for 48 hours. Conditioned media is removed and replaced with fresh media containing test compounds dissolved in DMSO (0.1% final concentration) and the cells are incubated for an additional 18 - 20 hours at 37° C. [3H]-thymidine is added to each well and allowed to incorporate into DNA for 4 hours. Unlabeled thymidine is then added to terminate the reaction, and the cultures are then washed, trypsinized and harvested. The amount of [3H]-thymidine incorporated into DNA is determined by liquid scintillation. Data for each well are expressed as a percent above control level, which is set at 100%. The concentration at which maximal deviation from control is found and the magnitude of that percent deviation is reported. Table T lists the data for some of the compounds of this invention.Cpd.# Concentration (µM) %control 27 0.7 224 30 7.0 204 38 5.0 189 43 1.0 151 45 5.0 191 53 1.0 50 63 10.0 94 70 10.0 173 78 0.1 112 81 10.0 56 85 4.0 215 88 10.0 187 124 0.08 462 113 0.71 470 122 1.0 105 123 0.79 387 117 5.0 160
Claims (6)
- A compound of the formula: whereinR1 is selected from the group consisting of hydrogen, halo, alkoxy (C1-C6) and hydroxy;R2 is alkyl (C1-C6);R3, R4 and R5 are selected from the group consisting of hydrogen, alkyl (C1-C6), alkoxy (C1-C6), benzyloxy, acyl (C2-C6), acyloxy (C2-C6), alkoxycarboxy wherein the alkoxy group has 1-5 carbon atoms, amino, acylamino (C2-C6), halo, nitro, hydroxy, cyano, alkylaminoalkoxy wherein the alkyl and alkoxy groups each contain 1-5 carbons, nitroso, dialkylphosphoryloxy, hydroxyalkyl (C1-C6), and phenyltetrazoyloxy;R6 and R7 are selected from hydrogen, alkyl (C1-C6), hydroxy, and when taken together alkylene (C1-C6) and carbonyl;R8 is selected from hydrogen, alkyl, hydroxy or acyloxy (C2-C6);R9 and R10 are hydrogen or together form a double bond, and R8 and R9 taken together form a carbonyl group, when R10 is hydrogen.
- A compound of claim 1 wherein R1 is selected from the group consisting of hydrogen, halo, alkoxy and hydroxy; R2 is alkyl; R3, R4 and R5 are selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxy, acyl, acyloxy, amino, acylamino, halo, nitro, hydroxy, and alkylaminoalkoxy; R6 and R7 are hydrogen, alkyl, alkylene, hydroxy or carbonyl; R8 is hydrogen,hydroxy or acyloxy; and R9 and R10 are hydrogen or together form a double bond .
- A compound of claim 1 selected from the group consisting of: 9-acetamido-6,11,11a,12-tetrahydro-6,11a-dimethyldibenz[a,f]azulene;2-fluoro-6,11,11a,12-tetrahydro-9-methoxy-6,11a-dimethyldibenz[a,f]azulene; 9-acetamido-6,11a-dimethyl-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene; 2-fluoro-4b,5,6,11,11a,12-hexahydro-9-hydroxy-6,11a-dimethyldibenz[a,f]azulene; 2-fluoro -4b,5,6,11,11a,12-hexahydro-9-methoxy-6,11a-dimethyldibenz[a,f]azulene; and 9- acetoxy-6, 11a-dimethyl-6,11,11a,12-tetrahydrodibenz[a,f]azulene.
- A compound of claim 1 selected from the group consisting of: 8-acetyl-4b,5,6,11,11a,12-hexahydro-6,11a-dimethyl-9-methoxydiben[a,f]azulene ; 6,11a-dimethyl-2-fluoro-8-nitro-9-methoxy-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene; 4b,5,6,11,11a,12-hexahydro-9-hydroxy-6,11a-dimethyl-8,10-dinitrodibenz[a,f]azulene ; 4b,5,6,11,11a,12-hexahydro-9-methoxy-6,11a-dimethyl-8-nitrodibenz[a,f]azulene; 6,11a-dimethyl-9-methoxy-8-nitro-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulenyl nitrate; and 6,11a-dimethyl-9-methoxy-10-nitro-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulenyl nitrate.
- A compound of claim 1 selected from the group consisting of: 6,11a-dimethyl-5,9-dihydroxy-8-nitro-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene; 6,11a-dimethyl-5-hydroxy-9-methoxy-8-nitro-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene; 9-amino-6,11a-dimethyl-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene; 6,11a-dimethyl-9-fluoro-4b,5,6,11,11a,12-hexahydrodibenz[a,f]azulene ; 6,11,11a,12-tetrahydro-9-methoxy-5,6,11a-trimethyldibenz[a,f]azulene; 7-methoxy-11a-methyl-6,11,11a,12-tetrahydrodibenz[a,f]azulene; and 9-methoxy-11a-methyl-6,11,11a,12-tetrahydrodibenz[a,f]azulene.
- The compound of any one of claims 1 to 5, for use in:(i) inducing ovulation in a female;(ii) controlling fertility in a female; or(iii) inhibiting spermatogenesis in a male.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40160395A | 1995-03-09 | 1995-03-09 | |
US401603 | 1995-03-09 | ||
PCT/US1996/002555 WO1996028403A1 (en) | 1995-03-09 | 1996-03-07 | SUBSTITUTED DIBENZ[a,f]AZULENES AND METHODS OF PREPARATION |
Publications (2)
Publication Number | Publication Date |
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EP0820426A1 EP0820426A1 (en) | 1998-01-28 |
EP0820426B1 true EP0820426B1 (en) | 2000-06-14 |
Family
ID=23588422
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP96908522A Expired - Lifetime EP0820426B1 (en) | 1995-03-09 | 1996-03-07 | SUBSTITUTED DIBENZ[a,f]AZULENES AND METHODS OF PREPARATION |
Country Status (12)
Country | Link |
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US (1) | US5834521A (en) |
EP (1) | EP0820426B1 (en) |
JP (1) | JP4027969B2 (en) |
AT (1) | ATE193878T1 (en) |
AU (1) | AU5173796A (en) |
CA (1) | CA2214894C (en) |
DE (1) | DE69608888T2 (en) |
DK (1) | DK0820426T3 (en) |
ES (1) | ES2148742T3 (en) |
GR (1) | GR3034269T3 (en) |
PT (1) | PT820426E (en) |
WO (1) | WO1996028403A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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DE19916837A1 (en) * | 1999-04-14 | 2000-10-19 | Merck Patent Gmbh | New di- or tetrahydro-benzoazulene derivatives, are integrin inhibitors useful e.g. for treating thrombosis, coronary heart disease, arteriosclerosis, tumors, osteoporosis or rheumatoid arthritis |
US6544918B1 (en) | 2001-07-17 | 2003-04-08 | Equistar Chemicals, Lp | Olefin polymerization catalysts containing chelating dianionic ligands |
US7179798B2 (en) * | 2001-11-16 | 2007-02-20 | Russell R. Roby | Methods and compositions for the treatment of pain and other hormone-allergy-related symptoms using dilute hormone solutions |
US20050065136A1 (en) * | 2003-08-13 | 2005-03-24 | Roby Russell R. | Methods and compositions for the treatment of infertility using dilute hormone solutions |
WO2005105107A2 (en) * | 2004-04-21 | 2005-11-10 | Roby Russell R | Hormone treatment of multiple sclerosis |
US20050239757A1 (en) * | 2004-04-21 | 2005-10-27 | Roby Russell R | Hormone treatment of macular degeneration |
US20060025390A1 (en) * | 2004-07-28 | 2006-02-02 | Roby Russell R | Treatment of hormone allergy and related symptoms and disorders |
-
1996
- 1996-03-07 CA CA002214894A patent/CA2214894C/en not_active Expired - Lifetime
- 1996-03-07 ES ES96908522T patent/ES2148742T3/en not_active Expired - Lifetime
- 1996-03-07 DE DE69608888T patent/DE69608888T2/en not_active Expired - Lifetime
- 1996-03-07 DK DK96908522T patent/DK0820426T3/en active
- 1996-03-07 JP JP52762996A patent/JP4027969B2/en not_active Expired - Lifetime
- 1996-03-07 PT PT96908522T patent/PT820426E/en unknown
- 1996-03-07 AU AU51737/96A patent/AU5173796A/en not_active Abandoned
- 1996-03-07 AT AT96908522T patent/ATE193878T1/en active
- 1996-03-07 EP EP96908522A patent/EP0820426B1/en not_active Expired - Lifetime
- 1996-03-07 WO PCT/US1996/002555 patent/WO1996028403A1/en active IP Right Grant
- 1996-08-05 US US08/693,861 patent/US5834521A/en not_active Expired - Lifetime
-
2000
- 2000-08-30 GR GR20000401956T patent/GR3034269T3/en unknown
Also Published As
Publication number | Publication date |
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JPH11502521A (en) | 1999-03-02 |
AU5173796A (en) | 1996-10-02 |
WO1996028403A1 (en) | 1996-09-19 |
CA2214894C (en) | 2008-05-13 |
EP0820426A1 (en) | 1998-01-28 |
ATE193878T1 (en) | 2000-06-15 |
US5834521A (en) | 1998-11-10 |
JP4027969B2 (en) | 2007-12-26 |
CA2214894A1 (en) | 1996-09-19 |
DE69608888T2 (en) | 2000-11-09 |
DE69608888D1 (en) | 2000-07-20 |
ES2148742T3 (en) | 2000-10-16 |
DK0820426T3 (en) | 2000-07-31 |
PT820426E (en) | 2000-09-29 |
GR3034269T3 (en) | 2000-12-29 |
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